人脑高时态分辨率正态发射断层扫描的放射跟踪器管理：在FDG-fPET中的应用
1Monash Biomedical Imaging,Monash University, 2Australian Research Council Centre of Excellence for Integrative Brain Function, 3Turner Institute for Brain and Mental Health,Monash University, 4Department of Medical Imaging,Monash Health, 5Department of Electrical and Computer Systems Engineering,Monash University
Summary
本手稿描述了 FDG-PET 的两个放射性跟踪器管理协议（恒定输注和 bolus 加输注），并将其与 bolus 给用进行比较。使用这些协议可实现 16 s 的时态分辨率。
Abstract
功能正电子发射断层扫描 （fPET） 提供了一种跟踪人脑中分子目标的方法。使用放射性标记的葡萄糖模拟物，18F-氟脱氧葡萄糖（FDG-fPET），现在可以通过接近功能磁共振成像（fMRI）的时间分辨率测量葡萄糖代谢的动态。这种直接的葡萄糖吸收量测量对于理解正常和异常的大脑功能以及探索代谢和神经退行性疾病的影响具有巨大的潜力。此外，混合MR-PET硬件的新进展使得使用fMRI和FDG-fPET同时捕获葡萄糖和血液氧合的波动成为可能。
FDG-fPET 图像的时间分辨率和信噪噪声在很大程度上取决于无线电跟踪器的管理。这项工作提出了两种替代的连续输注方案，并将其与传统博鲁斯方法进行比较。提出了一种采集血液样本、时间锁定PET、MRI、实验刺激以及管理非传统示踪剂输送的方法。使用视觉刺激，协议结果显示单个水平上对外部刺激的葡萄糖反应的皮质图，时间分辨率为16s。
Introduction
正电子发射断层扫描（PET）是一种强大的分子成像技术，广泛用于临床和研究环境（见Heurling等人1，最近进行了全面审查）。可以使用PET成像的分子靶点仅受放射性追踪器可用性的限制，并且已经开发出许多示踪剂来成像神经代谢受体、蛋白质和酶2、3。在神经科学中，最常用的放射性追踪器之一是18种F-氟氧葡萄糖（FDG-PET），它测量葡萄糖的吸量，通常被解释为脑葡萄糖代谢的指数。人脑需要恒定可靠的葡萄糖供应，以满足其能量需求4，5和70-80%的脑葡萄糖代谢被神经元在突触传播6使用。脑葡萄糖代谢的变化被认为是启动和促成许多情况，包括精神病，神经退行性，和缺血性条件7，8，9。此外，由于FDG的接受量与突触活性10、11、12成正比，与使用最广泛的血液相比，它被认为是神经元活性的更直接、更不混淆的指数氧合水平相关功能磁共振成像（BOLD-fMRI）响应。BOLD-fMRI是神经活动的间接指标，用于测量在神经元活动后发生一系列神经血管变化后发生的脱氧血红蛋白的变化。
大多数对人脑的FDG-PET研究获得脑葡萄糖摄取的静态图像。参与者在昏暗的房间里睁开眼睛，安静地休息了10分钟。完整的放射性追踪剂量在几秒钟内作为博鲁斯施用，然后参与者再休息30分钟。在摄取期之后，参与者被放置在 PET 扫描仪的中心，并获取反映摄取和扫描期间累积 FDG 分布的 PET 图像。因此，由 PET 图像索引的神经元活动表示所有认知活动在吸收和扫描期间以上的累积平均值，并不特定于扫描期间的认知活动。该方法对大脑大脑代谢和神经元功能提供了很好的见解。然而，时间分辨率等于扫描持续时间（通常为45分钟，有效地产生葡萄糖摄取的静态测量;这与认知过程中的神经元反应和神经成像中的常见实验相比是不利的。由于时间分辨率有限，该方法提供了葡萄糖摄入量的非特定指标（即，不锁定在任务或认知过程中），并且无法提供主体内变异性度量，这可能导致由于辛普森的悖论13。辛普森的悖论是一种情况，在这种情景中，跨主题计算的大脑行为关系并不一定表明受试者内部测试的相同关系。此外，最近尝试将功能连接措施应用于 FDG-PET 只能测量跨主体连接。因此，连接性的差异只能在组之间进行比较，不能针对各个主体计算。虽然究竟什么是跨主题连接性措施14尚存争议，但很显然，跨主题计算但非在受试者内的测量不能用作疾病状态的生物标志物，也不能用于检查个体变异的来源。
在过去五年中，临床级同步 MRI-PET 扫描仪的发展和更广泛的可访问性激发了对 FDG-PET 成像2认知神经科学的新研究兴趣。随着这些发展，研究人员专注于提高FDG-PET的时间分辨率，以接近BOLD-fMRI的标准（±0.5~2.5s）。请注意，BOLD-fMRI 的空间分辨率可以接近亚毫米分辨率，但由于正电子范围15，FDG-PET 的空间分辨率基本上限制在半最大 （FWHM） 时全宽约 0.54 mm。动态FDG-PET采集，在临床上经常使用，使用bolus管理方法，并将列表模式数据重建为bin。bolus动态FDG-PET方法提供大约100s的时间分辨率（例如，Tomasi等人16）。这显然比静态 FDG-PET 成像要好得多，但与 BOLD-fMRI 相比，效果不相上下。此外，检查大脑功能的窗口是有限的，因为FDG的血浆浓度在施用bolus后很快减少。
为了扩大这个实验窗口，少数研究17，18，19，20，21已经适应了无线电跟踪器输注方法之前提出的卡森22， 23.在此方法中，有时被描述为”功能 FDG-PET”（FDG-f PET，类似于 BOLD-f MRI），在整个 PET 扫描过程中，放射跟踪器作为持续输注进行管理（±90 分钟）。输注协议的目标是保持FDG的恒定血浆供应，以跟踪葡萄糖摄入量随时间的动态变化。在概念验证研究中，Villien等人21使用恒定输注协议和同时MRI/FDG-f PET显示葡萄糖摄入量的动态变化，以响应棋盘刺激，时间分辨率为60s。后续研究已使用此方法显示任务锁定的 FDG-fPET（即，时间锁定到外部刺激19）和与任务相关的 FDG-f PET（即，不锁定时间到外部刺激17，18）葡萄糖摄入量。利用这些方法，获得了60s的FDG-f PET时间分辨率，比bolus方法有了很大的改进。初步资料显示，输液方法可提供20~60s19的时间分辨率。
尽管恒定输注方法取得了可喜的结果，但这些研究的等离子体放射性曲线表明，输注方法不足以在90分钟的扫描19、21的时间内达到稳定状态。除了恒定的输注程序外，Carson22还提出了一种混合博鲁斯/输注程序，目标是在扫描开始时快速达到平衡，然后将等离子体放射性水平保持在平衡状态。扫描的持续时间。Rischka等人20最近使用20%的博鲁斯加80%的输注应用了这项技术。正如所料，动脉输入功能迅速上升到基线水平以上，并且以更高的速率维持更长时间，而使用输注程序19，21的结果。
本文介绍了使用输液和博鲁斯/输注放射跟踪器进行获取高时态分辨率FDG-f PET扫描的采集方案。这些协议已开发用于同时使用MRI-PET环境，采集时间为90-95分钟19。在协议中，采集血液样本以量化血浆血清放射性，以便随后对PET图像进行量化。虽然该协议的重点是使用BOLD-f MRI/FDG-f PET在功能神经成像中应用输注方法，但这些方法可以应用于任何FDG-f PET研究，而不管是否同时进行MRI，BOLD-fMRI，计算机断层扫描（CT），或其他神经图像被获取。图 1显示了此协议中过程的流程图。
Protocol
该协议已根据《澳大利亚关于人类研究中道德行为的国家声明24》经莫纳什大学人类研究伦理委员会（批准号CF16/1108- 2016000590）审查和批准。程序是在经认可的医学物理学家、核医学技术专家和临床放射技师的指导下开发的。研究人员应参考当地专家和人类电离辐射管理指南。 1. 所需的设备和人员 请参阅扫描仪室、放射化学实验室和一般材料的材料<…
Representative Results
研究特定方法在这里，报告具有代表性结果的研究特定细节。这些细节对程序并不重要，并且会因研究而异。 参与者和任务设计参与者（n = 3，表2）同时进行了BOLD-fMRI/FDG-f PET研究。由于本手稿侧重于 PET 采集协议，因此不会报告 MRI 结果。在95分钟的扫描过程中，参与?…
Discussion
FDG-PET是一种强大的成像技术，用于测量葡萄糖的摄取量，这是脑葡萄糖代谢的指标。迄今为止，大多数使用FDG-PET的神经科学研究都使用传统的bolus管理方法，静态图像分辨率表示扫描2过程中所有代谢活动的组成部分。本手稿描述了两种替代放射性追踪器管理协议：仅输液（例如，Villien等人、Jamadar等人19、21）和混合博鲁斯/输注（例?…
Disclosures
The authors have nothing to disclose.
Acknowledgements
Jamadar 获得澳大利亚研究委员会 （ARC） 发现早期职业研究员奖 （DECRA DE150100406） 的支持。Jamadar、Ward 和 Egan 由 ARC 综合脑功能卓越中心 （CE114100007） 提供支持。陈和李由瑞格伍德文化基金会资助。
贾马达尔、沃德、凯里和麦金太尔设计了协议。凯里、麦金太尔、萨桑和法伦收集了这些数据。贾马达尔、沃德、帕克斯和萨桑分析了这些数据。贾玛达尔、沃德、凯里和麦金太尔撰写了手稿的初稿。所有作者都审阅并批准了最终版本。
Materials
| Blood Collection Equipment | |||
| –12-15 vacutainers | Becton Dickinson, NJ USA | 364880 | Remain in sterile packaging until required to put blood in tube |
| –12-15 10mL LH blood collecting tubes | Becton Dickinson | 367526 | Marked with the sample number (e.g., S1, S2…) and subsequently marked with the sample time (e.g., time 0 + x min [T0+x]) |
| –2-15 10mL Terumo syringe | Terumo Tokyo, Japan | SS+10L | These are drawn up on the day of the study and capped with the ampoule that contained the saline |
| — pre-drawn 0.9% saline flushes | Pfizer, NY, USA | 61039117 | |
| –12-15 5mL Terumo syringes | Terumo Tokyo, Japan | SS+05S | Remain in sterile packaging until ready to withdraw a blood sample |
| Safety & Waste Equipment | All objects arranged on a plastic chair inside the scanner room on the same side as the arm from which the blood samples will be taken. Biohazard and non-biohazard waste bags to be used. Gloves and waste bags to be easily accessible when preparing the radioactivity in the dispensing area and when pipetting the plasma samples. Biohazard and non-biohazard waste bags to be used. All waste generated is checked with the Geiger counter to ensure that radioactive contaminated waste is stored until it is safe to be disposed of according to Australian Radiation Protection and Nuclear Safety Agency (APRANSA) guidelines for Radiation protection series No.6 (2017). | ||
| — Gloves | Westlab, VIC, Australia | 663-219 | |
| — waste bags | Austar Packaging, VIC, Australia | YIW6090 | |
| –cello underpads ‘blueys’ Underpads 5 Ply | Halyard Health, NSW, Australia | 2765A | |
| –Blue Sharpie pen | Sharpie, TN, USA | S30063 | |
| Dose Syringes | Remain in sterile packaging until ready for use. All syringes used in this facility have an additional 20% volume capacity above the stated volume on the packaging. This is important for the 50mL syringe where the total capacity of 60mL is used | ||
| –5mL | Terumo Tokyo, Japan | SS+05S | |
| — 20mL | Terumo Tokyo, Japan | SS+20L | |
| –50mL | Terumo Tokyo, Japan | SS*50LE | |
| –1 Terumo 18-gauge needle | Terumo Tokyo, Japan | NN+1838R | Remain in sterile packaging until ready to inject [18F]FDG into the saline bag |
| –100mL 0.9% saline bag | Baxter Pharmaceutical, IL, USA | AHB1307 | Remain in sterile packaging until ready to inject [18F]FDG |
| Radiochemistry Lab Supplies | |||
| –Heraeus Megafuge 16 centrifuge; Rotor Bioshield 720 | ThermoScientific MA, USA | 75004230 | Relative Centrifugal Force = 724 Our settings are 2000RPM for 5mins. Acceleration and deceleration curves set to 8 |
| –Single well counter | Laboratory Technologies, Inc. IL, USA | 630-365-1000 | Complete daily quality control (includes background count) and protocol set to 18F and 4mins. Cross calibration is performed between the well counter, dose calibrator and scanner on a bi-monthly basis. |
| –Pipette | ISG Xacto, Vienna, Austria | LI10434 | We use a 100-1000 μL set to 1000μL. It is calibrated annually. |
| –12-15 plasma counting tubes | Techno PLAS; SA Australia | P10316SU | Marked in the same manner as the LH blood tubes |
| –12-15 pipette tips | Expell Capp, Denmark | 5130140-1 | |
| –3 test tube racks | Generic | Checked with a Geiger counter to ensure there is no radiation contamination on them | |
| –500mL volumetric flask and distilled water | Generic | Need approximately 500mL of distilled water to prepare the reference for gamma counting | |
| –Synchronised clocks in scanner room, console and radiochemistry lab | Generic | Synchronisation checks are routinely completed in the facility on a weekly basis | |
| –Haemoglobin Monitor | EKF Diagnostic Cardiff, UK Haemo Control. | 3000-0810-6801 | Manufacturer recommended quality control performed before testing on participant’s blood sample. |
| –Glucometre | Roche Accu-Chek | 6870252001 | Accu-Chek Performa is used to measure participant blood sugar levels in mmol/L. Quality control is performed daily using high and low concentration solution control test. |
| Cannulating Equipment | Check expiry dates and train NMT to prepare aseptically for cannulation. | ||
| –Regulation tourniquet | CBC Classic Kimetec GmBH | K5020 | |
| –20, 22 and 24 gauge cannulas | Braun, Melsungen Germany | 4251644-03; 4251628-03; 4251601-03 | |
| –tegaderm dressings | 3M, MN USA | 1624W | |
| –alcohol and chlorhexidine swabs | Reynard Health Supplies, NSW Australia | RHS408 | |
| –0.9% saline 10mL ampoules; for flushes | Pfizer, NY, USA | 61039117 | |
| –10mL syringes | Terumo Tokyo, Japan | SS+10L | |
| –3-way tap | Becton Dickinson Connecta | 394600 | |
| –IV bung | Safsite Braun PA USA | 415068 | |
| –Optional extension tube, microbore extension set | M Devices, Denmark | IV054000 | |
| Scanner Room Equipment | |||
| –Siemens Biograph 3T mMR | Siemens, Erlangen, Germany | ||
| –Portable lead barrier shield | Gammasonics | Custom-built | MR-conditional lead barrier shield. Positioned at the 2000 Gauss line with the castors locked to provide additional shielding of the radioactivity connected to the infusion pump. |
| –Infusion pump BodyGuard 323 MR-conditional infusion pump | Caesarea Medical Electronics | 300-040XP | MR-compatible. This model is cleared for use on 1.5 and 3T scanners at 2000 Gauss with castors locked. |
| –Infusion pump tubing | Caesarea Medical Electronics | 100-163X2YNKS | Tubing is administration set with an anti-siphon valve and male luer lock (REF 100-163X2YNKS). |
| –Lead bricks | Custom built | Tested for ferromagnetic translational force | |
| Other Equipment | |||
| –Syringe shields | Biodex, NY USA | Custom-built | There is a 5mL tungsten syringe shield that is MR-safe, as well as a 50mL lead shield that has been tested for ferromagnetic attraction prior to use in the MR-PET scanner. It is used to transport the radioactive dose from the radiochemistry lab into the scanner to minimise radiation exposure to the NMT. |
| –Geiger counter Model 26-1 Integrated Frisker | Ludlum Measurements, Inc. TX USA | 48-4007 | This is calibrated annually and used to monitor potential contamination and waste. It is not taken into the MR-PET scanner. |
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Cite This Article
Jamadar, S. D., Ward, P. G., Carey, A., McIntyre, R., Parkes, L., Sasan, D., Fallon, J., Orchard, E., Li, S., Chen, Z., Egan, G. F. Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET. J. Vis. Exp. (152), e60259, doi:10.3791/60259 (2019).